Idiopathic myelofibrosis (IM) is a Philadelphia chromosome negative myeloproliferative disorder (MPD)[unreadable] thought to originate at the level of the muKipotent hematopoietic stem cell. The peripheral blood (PB) of IM[unreadable] patients contain greater numbers of hematopoietic stem cells (HSC) and progenitor cells (HPC) as well as[unreadable] endothelial progenitor cells (EPC) than normal individiduals. Since it is possible that the abnormal[unreadable] HSC/HPC/EPC trafficking in IM could be attributed to multiple pathological events, acting either alone or in[unreadable] combination, we intend to explore this pathological process by addressing the following hypotheses and[unreadable] objectives: Specific Aim 1: We will test the hypothesis that the abnormal CD34+ cell trafficking in IM is a[unreadable] consequence of defects in IM HSC/HPC/EPC that compromises the ability of these cells to be retained within[unreadable] the BM. Specific Aim 2: We will test the hypothesis that the abnormal CD34+ cell trafficking in IM is a[unreadable] consequence of the continuous release of proteases from IM BM HSC/HPC/EPC or their cellular progeny,[unreadable] which render the BM stem cell and/or vascular niches that maintain normal HSC/HPC/EPC homeostasis[unreadable] functionally defective. Since this abnormal HSC/HPC/EPC trafficking appears to be an integral part of the[unreadable] pathobiology of IM, we anticipate that greater understanding of this pathologic process will lead to the[unreadable] identification of therapeutic targets in the future against which novel drugs might be directed, allowing for[unreadable] improved treatment of IM, as well as the identification of additional biomarkers that might serve as indicators[unreadable] of disease activity. In addition, further insight into this pathological condition may also advance our[unreadable] understanding of normal HSC/HPC/EPC trafficking as well as cytokine-induced stem cell mobilization.[unreadable] Relevance:[unreadable] IM is a frequently fatal hematologic malignancy which is associated with increasing numbers of stem cells[unreadable] being present in the PB. We will attempt to dissect the causes of this abnormal HSC trafficking . Insight into[unreadable] this process will provide new targets for the development of therapeutic agents which will prevent the[unreadable] progression of the disease.